Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with end-stage renal disease (ESRD). Recent studies have demonstrated the critical role of inflammation, endothelial cell dysfunction, and oxidative injury in the development of cardiovascular disease. These factors appear to be of particular importance in the ESRD population, in whom several of these pathways are altered secondary to the metabolic consequences of renal dysfunction. These metabolic pathways include the L-arginine-nitric oxide (NO) pathway, the formation of methylated arginines via the protein arginine methyltransferase pathway and the methionine-homocysteine cycle. The overall aim of this study is to conduct a randomized, controlled, mechanistic study on the in vivo regulatory mechanisms of these metabolic pathways, and their influence on endothelial dysfunction in patients with CKD and ESRD assess the effects of these pathways on endothelial dysfunction in patients with ESRD and in healthy controls. We will, in addition, explore the nutritional-metabolic interactions of two nutrients found to exert significant influence on these pathways 1) supplementation with arginine and 2) supplementation with folic acid. We will also begin to explore the effect of two important functional genetic factors affecting these pathways: methylentetrahydrofolate reductase (MTHFR) and dimethylarginine dimethyl aminohydrolase (DDAH). Hence, the overall, long term objective is to obtain an integrated understanding of the metabolic, physiologic and genetic mechanisms that contribute to endothelial dysfunction of renal disease, with the ultimate goal of improvement in clinical outcomes of cardiovascular disease in these patients.